Acute Lymphoblastic Leukemia
Conditions
Keywords
Minimal Residual Disease, adult ALL, immunotherapeutic treatment, anti-CD19 bispecific antibody derivative, Blinatumomab, MT103
Brief summary
The purpose of this study is to determine whether the bispecific T-cell engager (BiTE®) Blinatumomab (MT103) is effective in the treatment of ALL patients with minimal residual disease.
Detailed description
The presence of leukemia cells below the cytological detection limit (5% leukemic cells) is defined as minimal residual disease (MRD). If no MRD is detectable (\< 10\^-4 = less than 1 leukemia cell per 10\^4 bone marrow cells) a complete molecular remission is reached. In the last years a series of retrospective studies has shown that MRD in adult ALL is an independent prognostic factor as already demonstrated for childhood leukemia. Diagnostic tools for MRD are polymerase chain reaction (PCR) and/or flow cytometry. PCR analysis can detect fusion transcripts such as bcr/abl and individual clonal rearrangements of immunoglobulins (IgH) and/or T-cell receptor genes (TCR). About 25% of patients with MRD defined by rearrangement comprise a high-risk group with a 94% relapse rate within 3 years. In general for patients with MRD, who are not eligible for allogenic stem cell transplantation, curative treatment is not available. This accounts for MRD defined by the Philadelphia chromosome translocation as well as for MRD defined by rearrangement. The current study is set up to address the question of treating MRD positive ALL with the bispecific anti-cluster of differentiation (CD)19 x anti-CD3 antibody derivative blinatumomab (MT103).
Interventions
BIOLOGICALBlinatumomab (MT103)
Administered by continuous intravenous (CIV) over 4 weeks per cycle
Sponsors
Amgen Research (Munich) GmbH
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* B-precursor ALL patients in complete hematological remission with molecular failure or molecular relapse starting at any time after consolidation I of front-line therapy within German Multicenter Study Group on Adult Acute Lymphoblastic Leukemia (GMALL) standards or at any time outside GMALL standards. * Patients must have a molecular marker for evaluation of minimal residual disease which is either Breakpoint cluster region/gene on human chromosome #9 (Bcr/abl) at any detection level or individual rearrangements of immunoglobulin or T-cell receptor (TCR)-genes measured by an assay with a sensitivity of minimum 10\^-4: At least one individual marker at a quantitative level ≥ 10\^-4. * Eastern Cooperative Oncology Group (ECOG) Performance Status \< 2 * Ability to understand and willingness to sign a written informed consent * Signed and dated written informed consent is available
Exclusion criteria
* Current extra medullar involvement * History of or current relevant central nervous system (CNS) pathology (except migraine/headache and/or previous infiltration of cerebrospinal fluid (CSF) by ALL) * Current infiltration of cerebrospinal fluid by ALL * History of or current autoimmune disease * Autologous stem cell transplantation within 6 weeks prior to study entry * Any prior allogeneic stem cell transplantation * Cancer chemotherapy within 4 weeks prior to study treatment (except for intrathecal prophylaxis and/or low dose maintenance therapy such as vinca alkaloids, mercaptopurine, methotrexate, steroids) * Radiotherapy within 4 weeks prior to study treatment * Therapy with monoclonal antibodies (Rituximab, MabCampath) within 6 weeks prior to study treatment * Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation * Presence of human anti-murine antibodies (HAMA) * Abnormal bone marrow, renal or hepatic function * Indication for a hypercoagulative state * History of malignancy other than ALL within 5 years prior to study entry, with the exception of basal cell carcinoma of the skin or cervix carcinoma in situ * Active severe infection, any other concurrent disease or medical condition that are deemed to interfere with the conduct of the study as judged by the investigator * Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HbsAg positive) or hepatitis C virus (anti-HCV positive) * Pregnant or nursing women * Women of childbearing potential not willing to use an effective form of contraception during participation in the study and at least 3 months thereafter or male patients not willing to ensure effective contraception during participation in the study and at least three months thereafter
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Minimal Residual Disease (MRD) Response Within 4 Cycles of Treatment | Within 4 treatment cycles, 24 weeks | MRD Response is defined as: * If Philadelphia Chromosome (Ph) positive (+) or translocation (t) (4;11), response was achieved when Ph or t(4;11) was below detection limit and individual rearrangements of immunoglobulin or T-cell receptor genes are below 10\^-4. * If Ph and t(4;11) negative, response was achieved when individual rearrangements of immunoglobulin or T-cell receptor genes are below 10\^-4. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Hematological Relapse | Up to the data cut-off date of 14 January 2010; maximum duration of follow-up was 564 days. | The time to hematological relapse is defined as the time between start of first infusion of blinatumomab and the first result of hematological relapse. Participants without an event of hematological relapse were censored on their last available date of bone marrow aspiration/biopsy. Hematological relapse is defined as \> 5% leukemia cells in bone marrow. Time to hematological relapse was analyzed using Kaplan-Meier methods. |
| Time to MRD Progression | Up to the data cut-off date of 14 January 2010; Median follow-up time was 155 days | Time to MRD progression is defined for participants who do not show MRD response at any time during the study as the time from start of first infusion until the first result of MRD progression or hematological relapse, if no MRD progression was diagnosed before hematological relapse. For participants who showed MRD response during the study the time to MRD progression is defined as the time from the date of the first MRD response to the date of MRD relapse. Participants without an event of MRD progression were censored on the day of their last bone marrow aspiration/biopsy. Participants who received a bone marrow transplant were censored on the last day of bone marrow aspiration/biopsy before transplantation. MRD progression is defined as the increase in the MRD level by 1 log as compared to the baseline level (equal to a 10-fold increase in the number of MRD cells), and had to be confirmed within 6 weeks. |
| Apparent Volume of Distribution | Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion. | — |
| Clearance of Blinatumomab | Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion. | — |
| Terminal Half-life of Blinatumomab | Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion. | — |
| Time to MRD Relapse | Up to the data cut-off date of 14 January 2010; Median follow-up time was 116.5 days | Time to MRD relapse is defined only for participants with an MRD response during the study, defined as the time between the date of the first MRD response and the date of MRD relapse. If a participant experienced hematological relapse without having shown MRD positivity before then the time point of MRD relapse is defined as the time point of hematological relapse. Participants without an event of MRD relapse or hematological relapse were censored on the day of their last available bone marrow aspiration/biopsy. If a participant received a bone marrow transplant the last day of bone marrow aspiration/biopsy before transplantation was used as time point for censoring. MRD relapse is defined as reappearance of bcr/abl, and/or t(4;11) translocation at any detection level, and/or by individual rearrangements of immunoglobulin or T-cell receptor genes ≥10\^-4 for at least 1 individual marker measured by an assay with a sensitivity of minimum 10\^-4 and should be confirmed within 6 weeks. |
| Percentage of Participants With an MRD Response After Each Treatment Cycle | At the end of each treatment cycle - Weeks 4, 10, 16, and 22. | MRD Response is defined as: * If Philadelphia Chromosome (Ph)+ or t(4;11), response was achieved when Ph or t(4;11) was below detection limit and individual rearrangements of immunoglobulin or T-cell receptor genes are below 10\^-4. * If Ph and t(4;11) negative, response was achieved when individual rearrangements of immunoglobulin or T-cell receptor genes are below 10\^-4. |
| Change From Screening Value in B-cell Count During Cycle 1 | At Screening and in Cycle 1 at the start of infusion, 45 minutes, 2, 6, 12, 24 hours and at Days 2, 7, 14, 21, 28 and 35 after the start of infusion. | B-cells were measured by flow cytometry. |
| Change From Screening Value in T-cell Count During Cycle 1 | At Screening and in Cycle 1 at the start of infusion, 45 minutes, 2, 6, 12, 24 hours and at Days 2, 7, 14, 21, 28 and 35 after the start of infusion. | T-cells were measured by flow cytometry. |
| Serum Cytokine Peak Levels in Cycle 1 | Cycle 1 at pre-dose and at post infusion start at 45 minutes; 2, 6, 12, 24, and 48 hours; 7, 14, 21, and 28 days. | The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN)-γ using fluorescence-activated cell sorter (FACS)-based cytometric bead array (CBA) system.The limit of detection (LOD) for the cytokine determination was 20 pg/mL, the limit of quantification (LOQ) was 125 pg/mL. |
| Serum Blinatumomab Concentration at Steady State | Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion. | The mean serum concentration of blinatumomab during cycle 1. The LOQ of the assay was 100 pg/mL, and the limit of detection (LOD) was 3 pg/mL. |
| Area Under the Drug Concentration-time Curve From Time Zero to Infinity | Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion. | — |
| Number of Participants With Adverse Events | From the start of study treatment until up to 4 weeks after the end of study treatment. The median treatment duration was 87.3 days. | The severity (or intensity) of AEs was evaluated according to the grading scale provided in the Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, or according to the following: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death. The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab. A serious adverse event (SAE) is any untoward medical occurrence or effect that, at any dose results in death, is life-threatening, requires or prolongs hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. In addition, all laboratory abnormalities of grade four severity that occur during or after administration of the investigational drug, any overdose and a pregnancy or fathering were reported as SAEs. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Blinatumomab Participants received blinatumomab as continuous intravenous infusion at constant flow rate over 4 weeks followed by a 2 week treatment-free period (defined as one treatment cycle), for up to a maximum of 10 cycles. The initial dose was 15 μg/m²/day. A dose increase to 30 μg/m²/day was permitted with evidence for insufficient response to blinatumomab treatment. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Hematological Relapse | 1 |
| Overall Study | Minimal Residual Disease Relapse | 1 |
| Overall Study | Patient was not Compliant | 1 |
| Overall Study | Received Bone Marrow Transplant | 6 |
Baseline characteristics
| Characteristic | Blinatumomab |
|---|---|
| Age, Continuous | 49.8 years STANDARD_DEVIATION 18.3 |
| Age, Customized 20-30 years | 3 participants |
| Age, Customized 31-40 years | 5 participants |
| Age, Customized 41-50 years | 2 participants |
| Age, Customized 51-60 years | 1 participants |
| Age, Customized 61-70 years | 7 participants |
| Age, Customized > 70 years | 2 participants |
| Genetic Alterations bcr/abl translocation above detection limit | 5 participants |
| Genetic Alterations Rearrangements of Ig / TCR genes only | 13 participants |
| Genetic Alterations Rearrangements of Ig / TCR genes & translocations | 3 participants |
| Genetic Alterations t(4;11) translocation above detection limit | 2 participants |
| Race/Ethnicity, Customized Caucasian | 20 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 21 / 21 |
| serious Total, serious adverse events | 10 / 21 |
Outcome results
Primary
Percentage of Participants With a Minimal Residual Disease (MRD) Response Within 4 Cycles of Treatment
MRD Response is defined as: * If Philadelphia Chromosome (Ph) positive (+) or translocation (t) (4;11), response was achieved when Ph or t(4;11) was below detection limit and individual rearrangements of immunoglobulin or T-cell receptor genes are below 10\^-4. * If Ph and t(4;11) negative, response was achieved when individual rearrangements of immunoglobulin or T-cell receptor genes are below 10\^-4.
Time frame: Within 4 treatment cycles, 24 weeks
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Blinatumomab | Percentage of Participants With a Minimal Residual Disease (MRD) Response Within 4 Cycles of Treatment | 80.0 percentage of participants |
p-value: 01-sided exact binomial test
Secondary
Apparent Volume of Distribution
Time frame: Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion.
Population: Participants who received at least 1 infusion of blinatumomab with available pharmacokinetic data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Blinatumomab | Apparent Volume of Distribution | 2.00 L/m² | Standard Deviation 0.95 |
Secondary
Area Under the Drug Concentration-time Curve From Time Zero to Infinity
Time frame: Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion.
Population: Participants who received at least 1 infusion of blinatumomab with available pharmacokinetic data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Blinatumomab | Area Under the Drug Concentration-time Curve From Time Zero to Infinity | 481 hr*ng/mL | Standard Deviation 106 |
Secondary
Change From Screening Value in B-cell Count During Cycle 1
B-cells were measured by flow cytometry.
Time frame: At Screening and in Cycle 1 at the start of infusion, 45 minutes, 2, 6, 12, 24 hours and at Days 2, 7, 14, 21, 28 and 35 after the start of infusion.
Population: Participants who received blinatumomab with available pharmacodynamic data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Blinatumomab | Change From Screening Value in B-cell Count During Cycle 1 | Start of infusion (N=19) | 0.0181 cells/μL | Standard Deviation 0.0803 |
| Blinatumomab | Change From Screening Value in B-cell Count During Cycle 1 | 45 minutes (N=19) | -0.0098 cells/μL | Standard Deviation 0.0402 |
| Blinatumomab | Change From Screening Value in B-cell Count During Cycle 1 | 2 hours (N=18) | -0.0361 cells/μL | Standard Deviation 0.0621 |
| Blinatumomab | Change From Screening Value in B-cell Count During Cycle 1 | 6 hours (N=19) | -0.0435 cells/μL | Standard Deviation 0.0685 |
| Blinatumomab | Change From Screening Value in B-cell Count During Cycle 1 | 12 hours (N=16) | -0.0417 cells/μL | Standard Deviation 0.0689 |
| Blinatumomab | Change From Screening Value in B-cell Count During Cycle 1 | 24 hours (N=18) | -0.0403 cells/μL | Standard Deviation 0.07 |
| Blinatumomab | Change From Screening Value in B-cell Count During Cycle 1 | Day 2 (N=17) | -0.0310 cells/μL | Standard Deviation 0.0589 |
| Blinatumomab | Change From Screening Value in B-cell Count During Cycle 1 | Day 7 (N=18) | -0.0462 cells/μL | Standard Deviation 0.0717 |
| Blinatumomab | Change From Screening Value in B-cell Count During Cycle 1 | Day 14 (N=18) | -0.0490 cells/μL | Standard Deviation 0.0745 |
| Blinatumomab | Change From Screening Value in B-cell Count During Cycle 1 | Day 21 (N=18) | -0.0494 cells/μL | Standard Deviation 0.0747 |
| Blinatumomab | Change From Screening Value in B-cell Count During Cycle 1 | Day 28 (N=17) | -0.0392 cells/μL | Standard Deviation 0.0634 |
| Blinatumomab | Change From Screening Value in B-cell Count During Cycle 1 | Day 35 (N=18) | -0.0493 cells/μL | Standard Deviation 0.0748 |
Secondary
Change From Screening Value in T-cell Count During Cycle 1
T-cells were measured by flow cytometry.
Time frame: At Screening and in Cycle 1 at the start of infusion, 45 minutes, 2, 6, 12, 24 hours and at Days 2, 7, 14, 21, 28 and 35 after the start of infusion.
Population: Participants who received blinatumomab with available pharmacodynamic data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Blinatumomab | Change From Screening Value in T-cell Count During Cycle 1 | Day 28 (N=17) | 0.1687 cells/μL | Standard Deviation 0.3119 |
| Blinatumomab | Change From Screening Value in T-cell Count During Cycle 1 | Start of infusion (N=19) | -0.0418 cells/μL | Standard Deviation 0.2925 |
| Blinatumomab | Change From Screening Value in T-cell Count During Cycle 1 | 45 minutes (N=19) | -0.3208 cells/μL | Standard Deviation 0.3137 |
| Blinatumomab | Change From Screening Value in T-cell Count During Cycle 1 | 2 hours (N=18) | -0.4976 cells/μL | Standard Deviation 0.3454 |
| Blinatumomab | Change From Screening Value in T-cell Count During Cycle 1 | 6 hours (N=19) | -0.5227 cells/μL | Standard Deviation 0.3432 |
| Blinatumomab | Change From Screening Value in T-cell Count During Cycle 1 | 12 hours (N=16) | -0.5390 cells/μL | Standard Deviation 0.3649 |
| Blinatumomab | Change From Screening Value in T-cell Count During Cycle 1 | 24 hours (N=18) | -0.4780 cells/μL | Standard Deviation 0.3774 |
| Blinatumomab | Change From Screening Value in T-cell Count During Cycle 1 | Day 2 (N=17) | -0.3328 cells/μL | Standard Deviation 0.3704 |
| Blinatumomab | Change From Screening Value in T-cell Count During Cycle 1 | Day 7 (N=18) | 0.1231 cells/μL | Standard Deviation 0.3051 |
| Blinatumomab | Change From Screening Value in T-cell Count During Cycle 1 | Day 14 (N=18) | 0.1172 cells/μL | Standard Deviation 0.4671 |
| Blinatumomab | Change From Screening Value in T-cell Count During Cycle 1 | Day 21 (N=18) | 0.1975 cells/μL | Standard Deviation 0.5596 |
| Blinatumomab | Change From Screening Value in T-cell Count During Cycle 1 | Day 35 (N=18) | 0.2271 cells/μL | Standard Deviation 0.3739 |
Secondary
Clearance of Blinatumomab
Time frame: Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion.
Population: Participants who received at least 1 infusion of blinatumomab with available pharmacokinetic data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Blinatumomab | Clearance of Blinatumomab | 0.939 L/hr/m² | Standard Deviation 0.199 |
Secondary
Number of Participants With Adverse Events
The severity (or intensity) of AEs was evaluated according to the grading scale provided in the Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, or according to the following: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death. The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab. A serious adverse event (SAE) is any untoward medical occurrence or effect that, at any dose results in death, is life-threatening, requires or prolongs hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. In addition, all laboratory abnormalities of grade four severity that occur during or after administration of the investigational drug, any overdose and a pregnancy or fathering were reported as SAEs.
Time frame: From the start of study treatment until up to 4 weeks after the end of study treatment. The median treatment duration was 87.3 days.
Population: Safety analysis set, including all participants who received ≥ 1 infusion of blinatumomab.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Blinatumomab | Number of Participants With Adverse Events | Related adverse events of at least CTC grade 3 | 13 participants |
| Blinatumomab | Number of Participants With Adverse Events | Adverse events of at least CTC grade 3 | 17 participants |
| Blinatumomab | Number of Participants With Adverse Events | Treatment-related adverse events | 21 participants |
| Blinatumomab | Number of Participants With Adverse Events | Serious adverse evets | 10 participants |
| Blinatumomab | Number of Participants With Adverse Events | Any adverse event | 21 participants |
| Blinatumomab | Number of Participants With Adverse Events | AEs leading to discontinuation of blinatumomab | 1 participants |
| Blinatumomab | Number of Participants With Adverse Events | Related serious adverse events | 9 participants |
| Blinatumomab | Number of Participants With Adverse Events | AEs leading to death | 0 participants |
Secondary
Percentage of Participants With an MRD Response After Each Treatment Cycle
MRD Response is defined as: * If Philadelphia Chromosome (Ph)+ or t(4;11), response was achieved when Ph or t(4;11) was below detection limit and individual rearrangements of immunoglobulin or T-cell receptor genes are below 10\^-4. * If Ph and t(4;11) negative, response was achieved when individual rearrangements of immunoglobulin or T-cell receptor genes are below 10\^-4.
Time frame: At the end of each treatment cycle - Weeks 4, 10, 16, and 22.
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Blinatumomab | Percentage of Participants With an MRD Response After Each Treatment Cycle | MRD negativity achieved after cycle 1 | 80.0 percentage of participants |
| Blinatumomab | Percentage of Participants With an MRD Response After Each Treatment Cycle | MRD negativity achieved after cycle 2 | 80.0 percentage of participants |
| Blinatumomab | Percentage of Participants With an MRD Response After Each Treatment Cycle | MRD negativity achieved after cycle 3 | 80.0 percentage of participants |
| Blinatumomab | Percentage of Participants With an MRD Response After Each Treatment Cycle | MRD negativity achieved after cycle 4 | 80.0 percentage of participants |
Secondary
Serum Blinatumomab Concentration at Steady State
The mean serum concentration of blinatumomab during cycle 1. The LOQ of the assay was 100 pg/mL, and the limit of detection (LOD) was 3 pg/mL.
Time frame: Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion.
Population: Participants who received at least 1 infusion of blinatumomab with available pharmacokinetic data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Blinatumomab | Serum Blinatumomab Concentration at Steady State | 696 pg/mL | Standard Deviation 147 |
Secondary
Serum Cytokine Peak Levels in Cycle 1
The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN)-γ using fluorescence-activated cell sorter (FACS)-based cytometric bead array (CBA) system.The limit of detection (LOD) for the cytokine determination was 20 pg/mL, the limit of quantification (LOQ) was 125 pg/mL.
Time frame: Cycle 1 at pre-dose and at post infusion start at 45 minutes; 2, 6, 12, 24, and 48 hours; 7, 14, 21, and 28 days.
Population: Safety analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Blinatumomab | Serum Cytokine Peak Levels in Cycle 1 | IL-2 | NA pg/mL | — |
| Blinatumomab | Serum Cytokine Peak Levels in Cycle 1 | IL-4 | NA pg/mL | — |
| Blinatumomab | Serum Cytokine Peak Levels in Cycle 1 | IL-6 | 693.2 pg/mL | Standard Deviation 1122.9 |
| Blinatumomab | Serum Cytokine Peak Levels in Cycle 1 | IL-8 | NA pg/mL | — |
| Blinatumomab | Serum Cytokine Peak Levels in Cycle 1 | IL-10 | 1135.3 pg/mL | Standard Deviation 1155.6 |
| Blinatumomab | Serum Cytokine Peak Levels in Cycle 1 | IFN-γ | 408.5 pg/mL | Standard Deviation 614.3 |
| Blinatumomab | Serum Cytokine Peak Levels in Cycle 1 | TNF-α | NA pg/mL | — |
Secondary
Terminal Half-life of Blinatumomab
Time frame: Cycle 1 at predose and at 2, 6, and 12 hours after start of infusion then weekly until end of the cycle, and at 1, 2, 4, 6, 8, and 24 hours after stop of infusion.
Population: Participants who received at least 1 infusion of blinatumomab with available pharmacokinetic data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Blinatumomab | Terminal Half-life of Blinatumomab | 1.47 hours | Standard Deviation 0.53 |
Secondary
Time to Hematological Relapse
The time to hematological relapse is defined as the time between start of first infusion of blinatumomab and the first result of hematological relapse. Participants without an event of hematological relapse were censored on their last available date of bone marrow aspiration/biopsy. Hematological relapse is defined as \> 5% leukemia cells in bone marrow. Time to hematological relapse was analyzed using Kaplan-Meier methods.
Time frame: Up to the data cut-off date of 14 January 2010; maximum duration of follow-up was 564 days.
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Blinatumomab | Time to Hematological Relapse | NA days |
Secondary
Time to MRD Progression
Time to MRD progression is defined for participants who do not show MRD response at any time during the study as the time from start of first infusion until the first result of MRD progression or hematological relapse, if no MRD progression was diagnosed before hematological relapse. For participants who showed MRD response during the study the time to MRD progression is defined as the time from the date of the first MRD response to the date of MRD relapse. Participants without an event of MRD progression were censored on the day of their last bone marrow aspiration/biopsy. Participants who received a bone marrow transplant were censored on the last day of bone marrow aspiration/biopsy before transplantation. MRD progression is defined as the increase in the MRD level by 1 log as compared to the baseline level (equal to a 10-fold increase in the number of MRD cells), and had to be confirmed within 6 weeks.
Time frame: Up to the data cut-off date of 14 January 2010; Median follow-up time was 155 days
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Blinatumomab | Time to MRD Progression | 221.0 days |
Secondary
Time to MRD Relapse
Time to MRD relapse is defined only for participants with an MRD response during the study, defined as the time between the date of the first MRD response and the date of MRD relapse. If a participant experienced hematological relapse without having shown MRD positivity before then the time point of MRD relapse is defined as the time point of hematological relapse. Participants without an event of MRD relapse or hematological relapse were censored on the day of their last available bone marrow aspiration/biopsy. If a participant received a bone marrow transplant the last day of bone marrow aspiration/biopsy before transplantation was used as time point for censoring. MRD relapse is defined as reappearance of bcr/abl, and/or t(4;11) translocation at any detection level, and/or by individual rearrangements of immunoglobulin or T-cell receptor genes ≥10\^-4 for at least 1 individual marker measured by an assay with a sensitivity of minimum 10\^-4 and should be confirmed within 6 weeks.
Time frame: Up to the data cut-off date of 14 January 2010; Median follow-up time was 116.5 days
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Blinatumomab | Time to MRD Relapse | NA days |